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(11) | EP 3 192 870 A1 |
(12) | EUROPEAN PATENT APPLICATION |
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(54) | MEDICAMENT FOR LIVER REGENERATION AND FOR TREATMENT OF LIVER FAILURE |
(57) The present invention relates to cultivated hepatocyte for blood purification, wherein
the hepatocyte contains a compound which is an inhibitor of the activity of MKK4,
MKK4 being encoded by SEQ ID NO: 1204. |
State of the art
Objects of the invention
General description of the invention
Detailed description of the invention
Fig. 1 schematic representations of nucleic acid constructs for producing inhibitory RNA,
Fig. 2 a schematic representation of a transposase mediated intrahepatic transfer of an expression cassette encoding an inhibitory RNA (micro RNA based shRNA) of the invention,
Fig. 3 the time course of the body weight of mice after stable transposon mediated intrahepatic transfer of an expression cassette for inhibitory RNA and controls, whereas an increase in body weight correlates with an increase in liver repopulation with the construct,
Fig. 4 GFP-imaging of explanted mouse livers in the process of repopulation by hepatocytes stably expressing shRNA specific for inactivating MKK4,
Fig. 5 a Western blot specific for MKK4 of liver samples of mice stably transfected with an expression cassette encoding shRNA specific for inactivating MKK4,
Fig. 6 immunofluorescence analysis of the livers of mice stably transfected with an expression cassette encoding shRNA specific for inactivating MKK4,
Fig. 7 a Western blot for cyclin A and E of nuclear liver extracts of transfected mouse livers in the indicated time course after partial hepatectomy indicating earlier cell cycle entry of hepatocytes stably expressing shRNA specific for MKK4,
Fig. 8 a Ki67 staining of mouse livers expressing shRNA specific for MKK4 or control shRNA at the indicated time points after partial hepatectomy,
Fig. 9 a quantifying graph of Ki67 positive hepatocytes depicted in Fig. 8,
Fig. 10 TUNEL (upper panel) and H&E staining (lower panel) on liver sections after induction of an acute/fulminant liver failure in control shRNA transfected hepatocytes in comparison to hepatocytes expressing an shRNA specific for RNA of MKK4, which are protected,
Fig. 11 a quantifying graph of apoptotic hepatocytes according to TUNEL staining as depicted in Fig 10,
Fig. 12 a survival curve of mice expressing the shRNA inactivating MKK4 (shMKK4) compared to control mice (shCtr.) after induction of liver failure,
Fig. 13 a quantifying graph of EdU incorporation into cultured murine hepatocytes with inactivated MKK4 activity (FAHIG-shMKK4) and control hepatocytes (FAHIG-shCtr) with an inset showing phase contrast micrographs of these hepatocytes,
Fig. 14 phase contrast micrographs of cultured hepatocytes with inactivated MKK4 (shMKK4) at day 29 (d29) and of control hepatocytes (shCtr) at day 12 (d12), and at day 3 of hepatocytes replated at day 15 (replating),
Fig. 15 a survival curve of FAH -/- mice after transplantation of hepatocytes kept one week in culture expressing shRNA specifically inactivating MKK4 or a control shRNA,
Fig. 16 photographs, GFP-imaging, α-FAH immunostaining and H&E staining of liver of mice aged for 1 year following transplantation of hepatocytes stably expressing shRNA specifically inactivating MKK4, and in
Fig. 17 an overview of the inhibitory effect of preferred small inhibitory compounds.
Example 1: Inactivation of MKK4 by transcription of inhibitory RNA from an expression cassette integrated into liver tissue
Example 2: Inhibition of MKK4 in vivo by transcription of inhibitory RNA from an expression cassette encoding shRNA
Example 3: Inhibition of MKK4 in vivo by inhibitory mRNA transfected into hepatocytes
Example 4: Inhibition of MKK4 in vivo by SP600125, myricitine, Genistein, or PD98059 in hepatocytes
Example 5: Inhibition of MKK4 in primary hepatocytes cultured in vitro by stable or transient transcription of inhibitory mRNA from an expression cassette encoding shRNA
Example 6: Cultured hepatocytes with inactivated MKK4 activity for use as a medicament for liver regeneration
Example 7: Cultivated hepatocytes with inactivated MKK4 activity for use as a device for extracorporal blood purification
Example 8: Inactivation of MKK4 in in vitro analyses
name | Structure | Inhibition, relative activity of MKK4 compared to control (without additional compound) (%) |
ZM 336372; 3-(Dimethylamino)-N-[3-[(4-hydroxybenzoyl)-amino]-4-methylphenyl]benza mide |
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54,2 |
BAS00525963; 2-hydroxy-1-methyl-4-oxo-N-pyridin-4-ylquinoline-3-carboxamide |
|
72,6 |
BAS00697444; 2-(1H-indazol-5-yliminomethyl)-6-nitrophenolate |
|
79,0 |
SYN22174524; 5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-7-oxo-N-phenyl-1H-pyrazolo[1, 5-a]pyrimidine-3-carboxamide |
|
47,8 |
SYN22174787; 5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-3-(4-fluorophenyl)-1H-pyrazolo[1, 5-a]pyrimidin-7-one |
|
41,5 |
SYN22175977; 5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-3-(4-methylphenyl)-1H-pyrazolo[1, 5-a]pyrimidin-7-one |
|
55,5 |
SYN22176267; 3-(4-chlorophenyl)-5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2-(methoxymethyl)-1H-pyrazolo[1,5-a]pyrimidin-7-one |
|
59,1 |
SYN22176367; 5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2-(methoxymethyl)-3-(4-methylphenyl)-1H-yrazolo[1,5-a]pyrimidin-7-one |
|
49,9 |
SYN22176842; 5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2-(3-methoxyphenyl)-3-methyl-pyrazolo[5,1-b]pyrimidin-7-ol |
|
54,9 |
SYN22176990; 5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2-(2-methoxyphenyl)-3-methyl-pyrazolo[5,1-b]pyrimidin-7-ol |
|
58,2 |
SYN22177890; 3-(4-chlorophenyl)-5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2-methyl-1H-Pyrazolo[1,5-a]pyrimidin-7-one |
|
56,3 |
BAS00896568; 5-amino-3-[(Z)-1-cyano-2-[3-[(4-methoxy-6-piperidin-1-yl-1,3, 5-triazin-2-yl)oxy]phenyl]etheny 1]-1-(2-hydroxyethyl)pyrazol e-4-carbonitrile |
|
58,4 |
BAS00697462; 2-(1H-indazol-5-yliminomethyl)-6-methoxy-4-nitrophenolate |
|
71,1 |
BAS00368055; 7-oxobenzo[e]-perimidine-4-carboxylic acid |
|
66,2 |
IUPAC Name: 1-phenyl-2-[[4-phenyl-5-[(5-phenyltetrazol-2-yl)methyl]-1,2, 4-triazol-3-yl]sulfanyl]ethanone |
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IUPAC Name: 2-[[5-[(2,4-dimethyl-anilino)methyl]-4-(furan-2-ylmethyl)-1,2,4-triazol-3-yl]sulfanylmethyl]-1H-quinazolin-4-one |
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N-(2-furylmethyl)-N-[1-(isopentylcarbamoyl) methyl]-5-(morpholinomethyl)-furan-2-carboxamide |
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IUPAC Name: 4-N-benzyl-1-N-[2-(3,4-dimethoxyphenyl)-ethyl]-4-N-ethylbenzene-1,4-disulfonamide |
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IUPAC Name: 3-[2-(2,5-dimethoxyphenyl)-2-oxoethyl]sulfanyl-6-methyl-2H-1,2,4-triazin-5-one |
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IUPAC Name: 2-[4-(4-methylbenzoyl)-piperidin-1-yl] sulfonylbenzoate |
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IUPAC Name: 2-[4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-2-methoxyphenoxy]-acetic acid |
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Popular Name: N-(6-ethoxy-1,3-benzothiazol-2-yl)-2-[[2-(p-tolyl)-9H-purin-6-yl]sulfanyl]acetamide |
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2-[4-(4-methoxyphenyl)-piperazia-1-yl]-N-(3-morpholino-sulfonyl-phenyl)-acetamide |
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Popular Name: 5-[[4-[(2,4,6-trioxohexahydropyrimidin-5-ylidene)methyl]-phenoxy]methyl]-furan-2-carboxylic |
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IUPAC Name: 3-(benzimidazol-1-yl)-N-[(2R)-1-[3-(3,4-difluorophenyl)-6-oxopyridazin-1-yl]butan-2-yl]propanamide |
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IUPAC Name: 2-methyl-3-(pyridin-3-ylmethylamino)benzo ate |
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IUPAC Name: N-[2-[[4-amino-6-(dimethylamino)-1,3,5-triazin-2-yl]oxy]ethyl]-2-(4-chloro-2-m ethylphenoxy)aceta mide |
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IUPAC Name: [3-ethoxy-4-(thiophen-2-ylmethoxy)phenyl]m ethyl-(2-morpholin-4-ium-4-ylethyl)azanium |
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IUPAC Name: 2-[4-(2-hydroxyethyl)piperaz in-1-yl]-N-(2-pyrrolidin-1-ylsulfonylethyl)pyridi ne-3-carboxamide |
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IUPAC Name: 1-[[2-(furan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]methyl-methylamino]-3-(4-methoxyphenoxy)propan-2-ol |
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IUPAC Name: N-ethyl-3-[2-(4-methoxyphenoxy)eth oxy]-N-(pyrazolo[1,5-a]pyrimidin-3-ylmethyl)aniline |
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IUPAC Name: N-ethyl-3-[2-(4-fluorophenoxy)ethox y]-N-[(2-methylpyrimidin-5-yl)methyl]aniline |
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IUPAC Name: 2-methoxy-5-morpholin-4-ylbenzoate |
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IUPAC Name: (1R,2S,3R)-3-(2-aminobenzoyl)-3-methyl-2-N-[(5-methyl-1,2,4-oxadiazol-3-yl)methyl]-1-N-(pyridin-4-ylmethyl)cyclopropan e-1,2-dicarboxamide |
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IUPAC Name: (2S,3S)-2,3-bis(ethoxycarbonyl)b utanedioate |
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IUPAC Name: diethyl 2-[(1,4-diethoxy-1,4-dioxobut-2-en-2-yl)amino]but-2-enedioate |
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IUPAC Name: (2S,3S)-2,3-bis(ethoxycarbonyl) butanedioate |
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IUPAC Name: diethyl 2-[(1,4-diethoxy-1,4-dioxobut-2-en-2-yl)amino]but-2-enedioate |
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IUPAC Name: 1-ethyl-2-hydroxy-N-(4-hydroxyphenyl)-4 -oxoquinoline-3 -carboxamide |
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IUPAC Name: 5-(phenylcarbamoyloxy)pentyl N-phenylcarbamate |
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Popular Name: N-[(5-acetamido-2-methoxy-phenyl)methyl]-2-morpholino-acetamide |
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IUPAC Name: 4-[4,6-bis(3-carboxypropyl)-1,3,5-trioxan-2-yl]butanoic acid |
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UPAC Name: methyl4-[(4-oxo-2-sulfanylidene-1,3-thiazolidin-5-ylidene)methyl]benz oate |
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IUPAC Name: 2-(3-methylanilino)-N-[(3-nitrophenyl)methylid eneamino]acetamide |
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IUPAC Name: [(2R)-2-[3-[bis[3-(dimethylazaniumyl) propyl]amino]propa noyloxy]-3-(dimethylamino)pro pyl]-dimethyl azanium |
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IUPAC Name 2-hydroxy-4-oxo-N-pyridin-4-yl-1H-quinoline-3-carboxamide |
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UPAC Name 1-ethyl-2-hydroxy-4-oxo-N-pyridin-4-ylquinoline-3-carboxamide |
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IUPAC Name: 2,3-bis[2-(2-nitrophenoxy)ethoxy ]-1,4-dioxane |
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4-hydroxy-2-oxo-N-(4-pyridinylmethyl)-1,2-dihydro-3-quinoline carboxamide |
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IUPAC Name: 7-oxobenzo[e]perimidi ne-4-carboxylic acid |
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IUPAC Name: 1,3-dioxobenzo[de]isoqu inoline-6-carboxylic acid |
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IUPAC Name: diethyl(2S)-2-[[3-[[(2S)-1,5-diethoxy-1,5-dioxopentan-2-yl]amino]-3-oxopropanoyl]amino ]pentanedioate |
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IUPAC Name: diethyl2-[[2-acetamido-3-(4-phenylmethoxyphen yl)propanoyl]amino] pentanedioate |
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IUPAC Name: 3-nitro-N-[(E)-[3-[(E)-[(3-nitrophenyl)hydrazin ylidene]methyl]phen yl]methylideneamin o]aniline |
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IUPAC Name: (4-methoxyphenyl)met hylN-[[4-[2-(3,4-dimethoxyphenyl)et hylamino]-4-oxobutan-2-ylidene]amino]carba mate |
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IUPAC Name: 3-amino-1,5-dihydropyrimido[5,4 -b]indole-2,4-dione |
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IUPAC Name: 1-[2-(2-fluorophenoxy)ethyl ]-3-[6-[2-(2-fluorophenoxy)ethyl carbamoylamino]hex yl]urea |
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IUPAC Name: methyl4-[[[2-[2-[2-[[4-[hydroxy(methoxy) methyl]phenyl]meth ylidene]hydrazinyl]-2-oxoethoxy]acetyl]hy drazinylidene]methy 1]benzoate |
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IUPAC Name: N-[2-(3,4-dimethoxyphenyl)et hyl]-2-quinolin-8-ylsulfanylacetamide |
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IUPAC Name: (2S,3S)-2,3-bis(4-butoxyphenoxy)-1,4-dioxane |
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IUPAC Name: 2-hydroxy-1-methyl-4-oxo-N-pyridin-4-ylquinoline-3-carboxamide |
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IUPAC Name: quinoline-2,4-dicarboxylic acid |
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IUPAC Name: 2-[(5Z)-5-[(3-hydroxyphenyl)meth ylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]propanoic acid |
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IUPAC Name: diethyl2-acetamido-2-[[5-amino-2-(2-ethoxy-2-oxoethoxy)phenyl]m ethyl]propanedioate |
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IUPAC Name: 4-[2-[2-[2-[(4-amino-1,2,5-oxadiazol-3-yl)oxy]ethoxy]ethox y]ethoxy]-1,2,5-oxadiazol-3-amine |
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IUPAC Name: (1R,2S,3S,4S )-2-(thiophen-2-ylmethylcarbamoyl) bicyclo[2.2.1]hept-5-ene-3-carboxylate |
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IUPAC Name: 3-[4-[2-[(4,4-dimethyl-2,6-dioxocyclohexyliden e)methylamino]ethyl ]piperazin-1-yl]-1-phenylpyrrolidine-2,5-dione |
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IUPAC Name: methyl4-[N-[2-(N-(4-methoxy-4-oxobutanoyl)anilino) ethyl]anilino]-4-oxobutanoate |
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IUPAC Name: 7-propan-2-ylidene-2-(pyridin-3-ylmethylcarbamoyl) bicyclo[2.2.1]hept-5-ene-3-carboxylic acid |
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1-[4-[2-hydroxy-3-(2-pyridylmethylamino )propoxy]phenoxy]-3-(2-pyridylmethylamino )propan-2-ol |
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IUPAC Name: 3-[5-[(4-hydroxyphenyl)meth ylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]propanoic acid |
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2-(1-benzothiazol-2-ylaminoiminoethylazo)benzoic |
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IUPAC Name: 2-[(3-acetylphenyl)-carbamoyl]bicycle-[2.2.1]hept-5-ene-3-carboxylate |
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IUPAC Name: 2-(1H-indazol-5-yliminomethyl)-6-nitrophenolate |
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IUPAC Name: 2-bromo-6-[(1H-indazol-5-ylamino)-methylidene]-4-nitrocyclohexa-2,4-dien-1-one |
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IUPAC Name: 2-(1H-indazol-5-yliminomethyl)-6-methoxy-4-nitrophenolate |
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N-{2-[2-(1-methyl-4-piperi dinyl idene)-hydrazino]-2-oxoethyl}-N-(3-nitrophenyl)benzene sulfonamide (non-preferred name) |
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IUPAC Name: 4-[5-(naphthalen-1-ylmethylidene)-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoate |
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IUPAC Name: 5-amino-3-[(Z)-1-cyano-2-[3-[(4-methoxy-6-piperidin-1-yl-1,3,5-triazin-2-yl)oxy]phenyl]ethen yl]-1-(2-hydroxyethyl)pyrazo le-4-carbonitrile |
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IUPAC Name: 8-[2-methoxy-4-[(1-oxo-[1,3]thiazolo[3,2-a]benzimidazol-2-ylidene)methyl]phen oxy]-1,3,7-trimethylpurine-2,6-dione |
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IUPAC Name: 2-[2-[2-(4-methylphenyl)sulfon ylethoxy]ethoxy]eth yl4-methylbenzenesulfo nate |
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IUPAC Name: (2S)-3-acetyl-4-hydroxy-1-(4-hydroxyphenyl)-2-phenyl-2H-pyrrol-5-one |
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IUPAC Name: bis[2-(3,4-dimethylphenyl)-2-oxoethyl] cyclohexane-1,2-dicarboxylate |
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IUPAC Name: 8-(butoxymethyl)-3-[2-[[5-(2-chlorophenyl)-1H-1,2,4-triazol-3-yl]sulfanyl]acetyl]-3-methyl-2,7-dioxaspiro[4.4]nona ne-1,6-dione |
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IUPAC Name: 2-(naphthalen-2-ylsulfonylamino)but anoic acid |
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1-(3,5-dimethoxyphenyl)-N-[(2-nitrophenyl)methyl] methanamine |
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IUPAC Name: 5-[(2-carboxylatophenyl)s ulfamoyl]-2-(3-carboxylatopropyla mino)benzoate |
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IUPAC Name: 2-(7H-purin-6-ylazaniumyl)acetate |
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IUPAC Name: [2-(4-bromophenyl)-2-oxoethyl]6-(5-methyl-2-oxo-1,3-dihydroimidazol-4-yl)-6-oxohexanoate |
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3-(2,3-dihydro-1H-indol-1-ylcarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid |
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IUPAC Name: benzyl-N-[2-[2-[(4-methoxy-3-nitrophenyl)-methylidene]-hydrazinyl]-2-oxoethyl]-N-methyl carbamate |
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IUPAC Name: methyl4-[[2-[2-[2-[(4-methoxy-4-oxobutyl)amino]-2-oxoethoxy]phenoxy] acetyl]amino]butano ate |
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IUPAC Name: [2-acetyloxy-4-[2-[5-(ethoxymethyl)-4-imino-2-methylpyrimidin-1-yl]acetyl]phenyl] acetate |
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IUPAC Name: (4-chloro-2-methylphenyl)methy lN-[2-[[4-(dimethylamino)-6-[methoxy(methyl)am ino]-1,3,5-triazin-2-yl]oxy]ethyl]carbam ate |
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1-[4-[2-hydroxy-3-(2-nitrophenoxy)-propyl]piperazin-1-yl]-3-(2-nitrophenoxy)-propan-2-ol |
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IUPAG Name: 2-[(5R)-3-(4-hydroxyphenyl)-2,4-dioxo-1,3-thiazolidin-5-yl] acetate |
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IUPAC Name: 2-[2-(2,4-dihydroxyphenyl)-2-oxoethyl]sulfanyl-4-hydroxy-1H-pyrimidin-6-one |
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IUPAC Name: 4-hydroxy-2-[2-(1H-indol-3-yl)-2-oxoethyl]sulfanyl-1H-pyrimidin-6-one |
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IUPAC Name: 3-(3-anilino-2-hydroxypropyl)-1-[[3-(3-anilino-2-hydroxypropyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl]-5,5-dimethylimidazolidi ne-2,4-dione |
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1-(2-furylmethy))-4-(3-nitrobenzyl)-piperazine |
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IUPAC Name: 2-nitro-6-[(5-pyridin-4-yl-1,3,4-thiadiazol-2-yl)carbamoyl]benzoi c acid |
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IUPAC Name: [2-[[[2-(4-phenylphenoxy)acet yl]hydrazinylidene] methyl]phenyl] acetate |
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2-((4'-HYDROXY-NAPHTHYL)-AZO)BENZOIC ACID |
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8-hydroxy-5,6-dihydro-4H-11-oxa-6a-azabenzo[de]anthrac ene-7,10-dione |
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IUPAC Name: 2-(pyridin-3-ylmethylcarbamoyl) bicyclo[2.2.1]hept-5-ene-3-carboxylate |
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4-Ethyl-5-(4-hydroxyphenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetic acid |
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IUPAC Name: 5-[[4-(benzylamino)-3-nitrophenyl]sulfonyl amino]benzene-1,3-dicarboxylate |
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IUPAC Name: 4-[4-(4-carboxylatophenoxy)phenyl]-sulfonylphthalate |
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N-[(2,4-dihydroxyphenyl)-methyleneamino]-2-[(8-methoxy-2-methyl-4-quinolyl)-sulfanyl]acetamide |
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IUPAC Name: 1-[2-[2-[2-[2-(2-acetyl-phenoxy)ethoxy]-ethoxy]ethoxy]-phenyl]ethanone |
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IUPAC Name: [2-[4-(4-chloro-2-nitro-phenoxy)phenyl]-2-oxoethyl] 2-benzami doacetate |
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IUPAC Name: phenacyl 3-[phenacyl-(phenacylamino)-amino]benzoate |
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IUPAC Name: 1-(4-amino-1,2,5-oxadiazol-3-yl)-5-(1H-benzimidazol-2-ylsulfanylmethyl)-N-[1-(5-nitrofuran-2-yl)ethylideneamino]-triazole-4-carboxamide |
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IUPAC Name: 2-benzamido-N-[1-(furan-2-ylmethylamino)-1-oxopropan-2-yl]benzamide |
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IUPAC Name: 2-benzamido-N-[1-(3-imidazol-1-ylpropy lamino)-1-oxo-3-phenylpropan-2-yl]benzamide |
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IUPAC Name: ethyl2-[[2-[2-(2,3-dioxoindol-1-yl)acetyl]oxyacetyl]-amino]-4-methyl-1,3-thiazole-5-carboxylate |
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IUPAC Name: ethyl5-[[5-ethoxycarbonyl-3-(2-methoxy-2-oxoethyl)-4-methyl-1H-pyrrol-2-yl]methyl]-4-(3-methoxy-3-oxopropyl)-3-methyl-1H-pyrrole-2-carboxylate |
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IUPAC Name: ethyl2-[[2-(1H-benzimidazol-2-ylsulfanyl)acetyl]-amino]-6-methyl-5,7-dihydro-4H-thieno[2,3-c]-pyridine-3-carboxylate |
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keto(3-pyridyl-methylcarbamoyl)-BLAHolate |
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keto(4-pyridylmethyl-carbamoyl)BLAHolate |
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hydroxy-oxo-N-(4-pyridyl)BLAH-carboxamide |
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IUPAC Name: 3-[[(5R)-2,4-dioxo-1,3-thiazolidin-5-yl]amino]benzoate |
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methyl N-acetyl-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-(2H-tetrazol-5-yl)norvalinate |
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IUPAC Name: 3-[(2,3-dioxo-1,4-dihydroquinoxalin-6-yl)sulfonyl]propanoa te |
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IUPAC Name: N-[2-(3,4-dimethoxyphenyl)et hyl]-2-[[5-[(4,6-dimethylpyrimidin-2-yl)sulfanyl-methyl]-1,3,4-oxadiazol-2-yl]-sulfanyl]acetamide |
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IUPAC Name: (2S)-1-(2,1,3-benzothiadiazol-4-ylsulfonyl)piperidine -2-carboxylic acid |
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benzyl(veratryl)-BLAH |
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IUPAC Name: 2-[1-(1,3-benzodioxol-5-yl)-2,5-dioxopyrrolidin-3-yl] sulfanylpyridine-3-carboxylate |
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IUPAC Name: 2-[4-(5-acetyl-1-hydroxy-4-methylimidazol-2-yl)-2-ethoxy-phenoxy]-N-(3-methylphenyl)-acetamide |
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(3-chlorophenyl)-keto-BLAH-carboxylate |
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1-naphthyl-oxo-BLAHcarboxylic acid |
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IUPAC Name: 2-(3,4-dimethoxyphenyl)-1 - [4-(2-fluorophenyl)-piperazin-1-yl]ethanone |
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IUPAC Name: 4-(4-ethoxyphenyl)-5-pyridin-4-yl-1,2,4-triazole-3-thiolate |
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IUPAC Name: 4-(3-methylphenyl)-5-pyridin-4-yl-1,2,4-triazole-3-thiolate |
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IUPAC Name: ethyl 2-(2-benzyl-sulfonylbenzimid-azol-1-yl)acetate |
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IUPAC Name: 2-[(3S)-1-(1,3-benzodioxol-5-yl)-2,5-dioxopyrrolidin-3-yl]sulfanyl-benzoate |
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Popular Name: 1-[3-(3-methoxy-phenoxy)propyl]-4-[(4-methylphenyl)-sulfonyl]piperazine |
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IUPAC Name: 3-(pyridin-3-ylmethyl-amino)benzoic acid |
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2-(4-hydroxy-phenyl)quinoline-4-carboxylic acid |
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IUPAC Name: 6-(2-pyridin-4-ylethylcarbamoyl)cy clohex-3-ene-1-carboxylate |
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IUPAC Name: 2-[(3S)-1-(4-hydroxyphenyl)-2,5-dioxopyrrolidin-3-yl]sulfanylbenzoate |
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IUPAC Name: 4-(4-methoxyphenyl)-5-pyridin-4-yl-1,2,4-triazole-3-thiolate |
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IUPAC Name: ethyl5-[(2R)-3-(3,5-dimethylpyrazol-1-yl)-2-hydroxy-propoxy]-1,2-dimethylindole-3-carboxylate |
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IUPAC Name: 1-naphthalen-2-yl-sulfonylpyrrolidine-2-carboxylic acid |
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IUPAC Name: (2S)-2-[(2,3-dioxo-1,4-dihydroquinoxalin-6-yl)sulfonyl-amino]propanoate |
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IUPAC Name: (2R)-3-acetyl-4-hydroxy-1-[2-(1H-indol-3-yl)ethyl]-2-pyridin-2-yl-2H-pyrrol-5-one |
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.2.1.0%1,5&]dec-8-ene-6-carboxylic acid |
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IUPAC Name: (3S)-3-(1H-indol-3-yl)-3-pyridin-4-ylpropanoic acid |
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IUPAC Name: 5-methyl-2-pyridin-4-yl-1H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one |
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IUPAC Name: (2S)-1-(1-methyl-2-oxobenzo[cd]indol-6-yl)sulfonylpyrrolidin e-2-carboxylic acid |
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IUPAC Name: [2-[4-(furan-2-carbonyloxy)phenyl] -2-oxoethyl]1-(furan-2-ylmethyl)-5-oxopyrrolidine-3-carboxylate |
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IUPAC Name: 4-[2-[5-(4-methoxyphenyl)-1H-pyrazol-4-yl]ethenyl]-6-(trifluoromethyl)-1H-pyrimidin-2-one |
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IUPAC Name: 2-hydroxy-5-[[(E)-(3-methyl-5-oxo-1H-pyrazol-4-ylidene)-methyl]amino]-benzoate |
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IUPAC Name: 3-oxo-2-(pyridin-4-ylmethyl)-1H-isoindole-4-carboxylic acid |
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8-hydroxy-[1]benzofuro[3,2-b]quinoline-11-carboxylic acid |
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IUPAC Name: 5-[[3-methoxy-4-(thiophen-2-ylmethoxy)phenyl]m ethylamino]-2-morpholin-4-ylbenzoate |
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oxylic acid |
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(3R)-4-keto-3-morpholin-4-ium-4-yl-4-(2-phenoxyethoxy)buty rate |
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(3R)-4-keto-3-morpholin-4-ium-4-yl-4-[[(2S)-tetrahydrofuran-2-yl]methoxy]butyrate |
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4-oxo-4-[2-[4-(p-tolylsulfonyl)-piperazin-1-yl]ethoxy]butanoic acid |
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IUPAC Name: 4-(3-chloro-4-fluorophenyl)-3-pyridin-4-yl-1H-1,2,4-triazole-5-thione |
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3-[3-(4-pyridyl)-5-thioxo-1H-1,2,4-triazol-4-yl]benzoic |
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IUPAC Name: 1-(3-phenyl-adamantane-1-carbonyl)pyrrolidine -2-carboxylic acid |
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IUPAC Name: 4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(3-hydroxyphenyl)-1H-1,2,4-triazole-5-thione |
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(dimethylBLAHyl)-methyl |
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IUPAC Name: N-[1-(3-imidazol-1-ylpropylamino)-3-methyl-1-oxobutan-2-yl]-2-[(4-methoxybenzoyl)amino]benz -amide |
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IUPAC Name: 1-ethyl-3-methyl-2-oxoquinoxaline-6-carboxylate |
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IUPAC Name: 3-(4-oxo-2H-pyrazolo[3,4-d]pyrimidin-1-yl)propanoate |
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3-(benzotriazol-1-yl)-1-[(3R)-3-[4-(3-methylisoxazol-5-yl)-2H-pyrazol-3-yl]-1-piperidyl]-propan-1-one |
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IUPAC Name: N-[2-(5-oxo-4-phenyltetrazol-1-yl)ethyl]-2-(4-oxo-3H-phthalazin-1-yl)acetamide |
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IUPAC Name: ethyl 4-[[4-(7-amino-2-methyl-pyrazolo[1,5-a]pyrimidin-5-yl)piperidin-1-yl]methyl]-3,5-dimethyl-1H-pyrrole-2-carboxylate |
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IUPAC Name: [4-(4-methyl-5-pyrimidin-4-yl-1,3-thiazol-2-yl)piperidin-1-yl]-(1H-1,2,4-triazol-5-yl)methanone |
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IUPAC Name: 3-methyl-1-phenyl-5-[(2-pyrrolidin-1-ylsulfonylethylamin o)methyl]-2H-pyrazolo[3,4-b]pyridin-6-one |
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1-[2-(4-methoxy-phenyl)pyrimidin-5-yl]-N-methyl-N-(4,5,6,7-tetrahydro-1H-indazol-3-ylmethyl)methan-amine |
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IUPAC Name: N-[[2-(4-methoxyphenyl)pyri midin-5-yl]methyl]-N-methyl-1-pyridin-2-ylpropan-2-amine |
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IUPAC Name: N-methyl-N-(2-phenoxyethyl)-2-quinazolin-4-yloxyacetamide |
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IUPAC Name: N-[2-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]ethyl]-2-[(5-methyl-1, 3,4-oxadiazol-2-yl)sulfanyl]-acetamide |
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IUPAC Name: 5-(2-ethoxypyridin-3-yl)-3-[2-(2-propan-2-ylpyrrolo[2,3-b]pyridin-1-yl)ethyl]-1,2,4-oxadiazole |
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IUPAC Name: N-[1-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-2-methylpropyl]-6-(2-hydroxyethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxamide |
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IUPAC Name: N-[2-(1-methyl-benzimidazol-2-yl)ethyl]-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenoxy]-acetamide |
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2-amino-5-[2-[4-[3-(2,3-dimethyl-phenoxy)propyl]-piperazin-1-yl]-2-oxo-ethyl]-6-methyl-3H-pyrimidin-4- |
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IUPAC Name: N-[1-(3,5-dimethyl-pyrazol-1-yl)propan-2-yl]-1-(1,5-dimethylpyrazol-4-yl)sulfonylpiperidine -4-carboxamide |
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IUPAC Name: 4-[(3,5-dimethylpyrazol-1-yl)methyl]-N-[2-(4-fluorophenoxy)-phenyl]-5-methyl-1,2-oxazole-3-carboxamide |
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IUPAC Name: 2-(3-methyl-2,6-dioxopurin-7-yl)-N-[1-(7-methyl-1H-indol-3-yl)propan-2-yl]acetamide |
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IUPAC Name: 7-bicyclo[4.1.0]-heptanyl-[4-[3-(2-methoxyphenoxy)-propyl]piperazin-1-yl]methanone |
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IUPAC Name: 5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-7-oxo-N-phenyl-1H-pyrazolo[1,5-a]pyrimidine-3-carboxamide |
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IUPAC Name: 5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-3-(4-fluoro-phenyl)-1H-pyrazolo-[1,5-a]pyrimidin -7-one |
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IUPAC Name: 5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-3-(4-methylphenyl)-1H-pyazolo[1,5-a]-pyrimidin-7-one |
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IUPAC Name: 5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-2-(methoxy-methyl)-3-phenyl-1H-pyrazolo [1,5-a]pyrimidin-7-one |
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IUPAC Name: 3-(4-chlorophenyl)-5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2-(methoxymethyl)-1H-pyrazolo[1,5-a]-pyrimidin-7-one |
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IUPAC Name: 5-[2-(3,5-dimethyl-1H-pyrazo 1-4-yl)ethyl]-2-(methoxymethyl)-3-(4-methylphenyl)-1H-pyrazolo [1,5-a]pyrimidin-7 -one |
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2-(3,4-dimethoxyphenyl)-5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]pyrazolo-[5,1-b]pyrimidin-7-ol |
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5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2-(3-methoxyphenyl)-3-methyl-pyrazolo[5,1-b]pyrimidin-7-ol |
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5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2-(2-methoxyphenyl)-3-methyl-pyrazolo[5,1-b]pyrimidin-7-ol |
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5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-3-methyl-2-(2-thienyl)pyrazolo[5,1-b]pyrimidin-7-ol |
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IUPAC Name: 3-(4-chlorophenyl)-5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-2-methyl-1H-pyrazolo[1,5-a]-pyrimidin-7-one |
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IUPAC Name: 5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl] -2-methyl-3-phenyl-1H-pyrazolo[1,5-a]-pyrimidin-7-one |
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5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-2-(4-fluorophenyl)-pyrazolo[5,1-b]pyrimidin-7-o |
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IUPAC Name: 3-(4-chlorophenyl)-5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-1H-pyrazolo-[1,5-a]pyrimidin-7-one |
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REFERENCES CITED IN THE DESCRIPTION
Patent documents cited in the description